This invention provides a process for preparing key intermediates useful for the preparation of heterocyclic compounds. Such compounds include, but are not limited to azacyclic and azabicyclic compounds which are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease.
The process of this invention is particularly useful for preparing intermediates which are useful for making compounds of formula I'. The formula I' compounds exhibit muscarinic cholinergic agonist activity. Such compounds have the following structure: ##STR2## wherein W is oxygen or sulphur,
R is hydrogen, amino, halogen, NHR.sup.6 NR.sup.6 R.sup.7, R.sup.4, --OR.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2 R.sup.4, C.sub.3-10 -cycloalkyl, C.sub.4-12 -(cycloalkylalkyl), --Z--C.sub.3-10 -cycloalkyl and --Z--C.sub.4-12 -(cycloalkylalkyl) wherein R.sup.4 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), --CF.sub.3, --CN, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CH.sub.3, --CONH.sub.2 or --CSNH.sub.2 ; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 or --CSNH.sub.2 ; or PA1 R is --OR.sup.5 Y, --SR.sup.5 Y, OR.sup.5 --Z--Y, --SR.sup.5 ZY, --O--R.sup.5 --Z--R.sup.4 or --S--R.sup.5 --Z--R.sup.4 wherein Z is oxygen or sulphur, R.sup.5 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, and Y is a 5 or 6 membered heterocyclic group; and PA1 G is selected from one of the following azacyclic or azabicyclic ring systems: ##STR3## or G can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6 R.sup.7 ; PA1 R.sup.6 and R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl, R.sup.6 and R.sup.7 together with the nitrogen atom optionally form a 4- to 6-member ring; PA1 R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, C.sub.1-5 -alkyl substituted with --OH, --COR.sup.6', CH.sub.2 --OH, halogen, --NH.sub.2, carboxy, or phenyl; PA1 R.sup.3 is hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl or C.sub.2-5 -alkynyl; PA1 n is 0, 1 or 2; PA1 m is 0,1 or 2; PA1 p is 0, 1 or 2; PA1 q is 1 or 2; PA1 r is 0, 1 or 2; PA1 ....... is a single or double bond. PA1 R.sup.4 is selected from the group consisting of C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF.sub.3, --CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, or --CF.sub.3 ; or PA1 R' is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, and --CF.sub.3 ; or PA1 R' selected from the group consisting of --OR.sup.5 Y, --SR.sup.5 Y, OR.sup.5 --Z--Y, --SR.sup.5 ZY, --O--R.sup.5 --Z--R.sup.4 and --S--R.sup.5 --Z--R.sup.4 ; PA1 Z is oxygen or sulphur, PA1 R.sup.5 is selected from the group consisting of C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, and C.sub.2-15 -alkynyl; PA1 Y is a 5 or 6 membered heterocyclic group; PA1 R.sup.1' is selected from the group consisting of phenyl, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl and (NR.sup.2').sub.3 ; PA1 R.sup.2' and R.sup.3' are independently selected from the group consisting of hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, and C.sub.1-5 -alkyl substituted with one or more selected from the group consisting of halogen and phenyl; PA1 W is oxygen or sulphur; PA1 G is selected from one of the following azacyclic or azabicyclic ring systems: ##STR5## or G can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6 R.sup.7 ; PA1 R.sup.6, and R.sup.7 independently are C.sub.1-6 -alkyl; or PA1 R.sup.6 and R.sup.7 together with the nitrogen atom optionally form a 4- to 6-member ring; PA1 R.sup.1 and R.sup.2 are independently selected from hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, and C.sub.1-5 -alkyl substituted with one or more independently selected from the group consisting of --COR.sup.6', halogen, and phenyl; PA1 R.sup.6' is hydrogen or C.sub.1 -C.sub.3 alkyl; PA1 R.sup.3 is selected from the group consisting of C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl and C.sub.2-5 -alkynyl; PA1 n is 0, 1 or 2; PA1 m is 0, 1 or 2; PA1 p is 0, 1 or 2; PA1 q is 1 or 2; PA1 r is 0, 1 or 2; PA1 ....... is a single or double bond; PA1 R.sup.4 is selected from the group consisting of C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF.sub.3, --CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, or --CF.sub.3 ; or PA1 R.sup.5 is selected from the group consisting of C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, and C.sub.2-15 -alkynyl; PA1 Y is a 5 or 6 membered heterocyclic group; PA1 G is selected from one of the following azacyclic or azabicyclic ring systems: ##STR8## or G can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6 R.sup.7 ; PA1 R.sup.6, and R.sup.7 independently are C.sub.1-6 -alkyl; or PA1 R.sup.6 and R.sup.7 together with the nitrogen atom optionally form a 4- to 6-member ring; PA1 R.sup.1 and R.sup.2 are independently selected from hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, and C.sub.1-5 -alkyl substituted with one or more independently selected from the group consisting of --COR.sup.6', halogen, and phenyl; PA1 R.sup.6' is hydrogen or C.sub.1 -C.sub.3 alkyl; PA1 R.sup.3 is selected from the group consisting of C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl and C.sub.2-5 -alkynyl; PA1 n is 0, 1 or 2; PA1 m is 0,1 or 2; PA1 p is 0,1 or 2; PA1 q is 1 or 2; PA1 r is 0, 1 or 2; PA1 ....... is a single or double bond; PA1 R.sup.1 and R.sup.2 independently are selected from the group consisting of hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, and C.sub.1-5 -alkyl substituted with one or more independently selected from the group consisting of --COR.sup.6', halogen, and phenyl; PA1 R.sup.6' is hydrogen or C.sub.1 -C.sub.3 alkyl; PA1 R.sup.3 is selected from the group consisting of C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl and C.sub.2-5 -alkynyl; PA1 n is 0, 1 or 2; PA1 m is 0, 1 or 2; PA1 p is 0, 1 or 2; PA1 q is 1 or 2; PA1 r is 0, 1 or 2; PA1 ....... is a single or double bond; PA1 R.sup.6 and R.sup.7 independently are C.sub.1-6 -alkyl; or PA1 R.sup.6 and R.sup.7 together with the nitrogen atom optionally form a 4- to 6-member ring; PA1 R.sup.19 is selected from the group consisting of R.sup.7, --OR.sup.7, --SR.sup.7, --SOR.sup.7, --SO.sub.2 R.sup.7, C.sub.3-10 -cycloalkyl, C.sub.4-12 -(cycloalkylalkyl), --Z--C.sub.3-10 -cycloalkyl and --Z--C.sub.4-12 -(cycloalkylalkyl); PA1 R.sup.7 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF.sub.3, --CN, Y, phenyl and phenoxy; wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, and --CF.sub.3 ; PA1 Y is a 5 or 6 membered heterocyclic group; PA1 Z is oxygen or sulphur; PA1 R.sup.8 is selected from the group consisting of C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl and C.sub.2-15 -alkynyl; PA1 aryl and heteroaryl is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, C.sub.1-4 -alkylthio, C.sub.1-4 -alkylsulfone, C.sub.1-4 -alkylsulfoxide, --OCF.sub.3, NO.sub.2, N(R.sup.7).sub.2, and --CF.sub.3 ; PA1 R.sup.15 is selected from the group consisting of aryl and heteroaryl; wherein aryl or heteroaryl is optionally independently substituted with one or more selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, C.sub.1-4 -alkylthio, C.sub.1-4 -alkylsulfone, C.sub.1-4 -alkylsulfoxide, --OCF.sub.3, NO.sub.2, N(R.sup.7).sub.2, and --CF.sub.3 ; PA1 R.sup.4 is selected from the group consisting of C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF.sub.3, --CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, or --CF.sub.3 ; or PA1 R' is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, and --CF.sub.3 ; or PA1 R' selected from the group consisting of --OR.sup.5 Y, --SR.sup.5 Y, OR.sup.5 --Z--Y, --SR.sup.5 ZY, --O--R.sup.5 --Z--R.sup.4 and --S--R.sup.5 --Z--R.sup.4 ; PA1 Z is oxygen or sulphur; PA1 R.sup.5 is selected from the group consisting of C.sub.1-15 -alkyl, PA1 C.sub.2-15 -alkenyl, and C.sub.2-15 -alkynyl; PA1 Y is a 5 or 6 membered heterocyclic group; PA1 R.sup.1' is selected from the group consisting of phenyl, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl and (NR.sup.2').sub.3 ; PA1 R.sup.2' and R.sup.3' are independently selected from the group consisting of hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, and C.sub.1-5 -alkyl substituted with one or more selected from the group consisting of halogen and phenyl; PA1 W is oxygen or sulphur; PA1 G is selected from one of the following azacyclic or azabicyclic ring systems: ##STR15## or G can optionally be substituted C.sub.3 -C.sub.8 cycloalkyl or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6 R.sup.7 ; PA1 R.sup.6, and R.sup.7 independently are C.sub.1-6 -alkyl; or PA1 R.sup.6 and R.sup.7 together with the nitrogen atom optionally form a 4- to 6-member ring; PA1 R.sup.1 and R.sup.2 are independently selected from hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, and C.sub.1-5 -alkyl substituted with one or more independently selected from the group consisting of --COR.sup.6', halogen, and phenyl; PA1 R.sup.6' is hydrogen or C.sub.1 -C.sub.3 alkyl; PA1 R.sup.3 is selected from the group consisting of C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl and C.sub.2-5 -alkynyl; PA1 n is 0, 1 or 2; PA1 m is 0, 1 or 2; PA1 p is 0, 1 or 2; PA1 q is 1 or 2; PA1 r is 0, 1 or 2; PA1 ....... is a single or double bond; PA1 R.sup.7 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF.sub.3, --CN, Y, phenyl and phenoxy; wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, and --CF.sub.3 ; PA1 Y is a 5 or 6 membered heterocyclic group; PA1 Z is oxygen or sulphur; PA1 R.sup.8 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl;
The present invention provides a process for making key intermediates which are useful for making heterocyclic compounds.
Further, the process may be completed via a convenient, one pot synthesis. Certain of the processes claimed herein provide a method for inverting the stereochemistry at the carbon bearing the hydroxyl group in the G substituent described supra. Such inverted stereochemistry can be important for the commercial development of pharmaceutically active compounds.